University of Queensland researchers have made a significant step towards enabling women with epilepsy safer access to Sodium Valproate, a common and highly effective anti-seizure medication. Sodium Valproate, or valproic acid, is widely prescribed for epilepsy and certain mental health conditions, but is considered harmful to use during pregnancy because of links to spinal cord defects and other complications for newborns.
Organoids Reveal Valproate's Mechanism
Dr. Giovanni Pietrogrande and Professor Ernst Wolvetang from UQ’s Australian Institute for Bioengineering and Nanotechnology (AIBN) led a team of organoid experts who have identified a drug that could nullify the dangerous side effects. The team created organoids – human mini-spinal cords in a dish – that closely mimic the spinal cord of a fetus in the early weeks of gestation. When these mini spinal cords were exposed to valproate, the team discovered that the drug changes the cells that normally form the spinal cord, leading to malformations.
"We first set out to understand why valproate causes spinal cord malformations in fetuses," Dr. Pietrogrande said. "To do this we created organoids – human mini-spinal cords in a dish – that closely mimic the spinal cord of a fetus in the early weeks of gestation. When these mini spinal cords were exposed to valproate, the team discovered that the drug changes the cells that normally form the spinal cord, leading to malformations."
Rapamycin Prevents Valproate's Effects
Professor Wolvetang said the AIBN team then treated the organoids with the clinically approved drug Rapamycin, and found it prevented the negative effects of valproic acid.
"Therefore co-treatment with Rapamycin could be the thing that opens safe access to an extremely effective treatment for women with epilepsy," Professor Wolvetang said.
Clinical Implications
Study co-author Professor Terence O’Brien, Head of the School of Translational Medicine at Monash University and program director and deputy director of research at Alfred Brain, said the findings could help healthcare providers and patients navigate the complex challenges around the treatment of epilepsy. "It may also provide a pathway to enabling women to continue to take this life saving medication while having healthy children," Professor O’Brien said.
Organoids as a Tool for Drug Discovery
Professor Wolvetang said the research highlights the potential of new technologies like human stem cell derived organoids to explore the molecular and cellular impacts of drugs. "Organoids are a tool that allow us to develop new treatments, and also to uncover new ways to improve the safety and efficacy of existing ones," he said. "We hope this research is another step towards fostering regulatory change in the Therapeutic Goods Administration (TGA) to establish organoids as a powerful tool for drug screening and discovery."
The research, published in Molecular Psychiatry, demonstrates that valproic acid induces extensive cellular senescence and promotes mesenchymal differentiation of human neural crest cells (NCCs). The study further identifies the pioneer factor AP1 as a key element of this process, suggesting cellular senescence as a central driver of VPA-associated neurodevelopmental teratogenicity and identifies a new pharmacological strategy for prevention.
